ω-Nor-aromatic-13,14-dehydro-prostaglandins and process for their preparation

ABSTRACT

PGF.sub.α compounds are disclosed having as the lower side chain ##STR1## in which one of R 4  and R 5  hydroxyl and the other is alkoxy R 6  is hydrogen or alkyl, m is 0-3, E represents oxygen or sulphur and R is hydrogen, halogen, alkyl, alkoxy or trihaloalkyl.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of our application Ser. No. 833,609filed Sept. 15, 1977, which in turn is a divisional of application Ser.No. 786,802, filed Apr. 12, 1977.

The present invention relates toω-nor-aromatic-13,14-dehydro-prostaglandins to a method for theirpreparation and to pharmaceutical and veterinary compositions containingthem.

The compounds of the invention are optically active or racemicprostaglandins of formula (I) ##STR2## wherein

A is a member selected from the group consisting of (a) --CH₂ OH; (b)--COOR_(a), wherein R_(a) is hydrogen, a C₁ -C₁₂ alkyl group or a cationof a pharmaceutically or veterinarily acceptable base; (c) ##STR3##wherein R_(b) and R_(c) are independently selected from the groupconsisting of hydrogen, C₁ -C₆ alkyl and phenyl;

the symbol represents a single or a double bond, wherein, when thesymbol is a double bond, R₃ is a hydrogen atom and R₁ and R₂ togetherform an oxo group, while, when the symbol is a single bond, R₃ ishydroxy and one of R₁ and R₂ is hydrogen and the other is hydroxy oracyloxy or R₁ and R₂, taken together, form an oxo group;

one of R₄ and R₅ is hydrogen and the other is hydroxy, C₁ -C₆ alkoxy oraralkoxy;

R₆ is hydrogen or C₁ -C₄ alkyl;

B is --(CH₂)_(n) -- or --(CH₂)_(m).sbsb.1 --E--(CH₂)_(m).sbsb.2 --,wherein each of n, m₁ and m₂ is independently zero, 1, 2 or 3 and E isoxygen or sulphur;

R is a member selected from the group consisting of (a') C₁ -C₆ alkyl;(b') C₁ -C₆ alkoxy; (c') C₁ -C₆ trihaloalkyl; (d') halogen; (e') amino;(f') ##STR4## wherein R_(d) and R₃ are independently selected from thegroup consisting of hydrogen, phenyl, benzoyl, C₁ -C₆ alkyl, C₁ -C₆aliphatic acyl; (g') phenyl, unsubstituted or substituted by one or moresubstituents selected from the group consisting of C₁ -C₆ alkoxy andhalogen; and (h') phenoxy, unsubstituted or substituted by one or moresubstituents selected from the group consisting of C₁ -C₆ alkoxy andhalogen.

The double bond in the 5(6)-position is a cis-double bond.

In the formulae of this specification, the broken lines ( ) indicatethat the substituents are in the α-configuration, i.e. are below theplane of the ring or of the chain, while the heavy solid lines ( )indicate that the substituents are in the β-configuration, i.e. abovethe plane of the ring or of the chain; the wavy line attachment ( )indicates that the groups may be either in the α-configuration, or inthe β-configuration.

As is evident from formula (I), the hydroxy group, or respectively theC₁ -C₆ alkoxy or the aralkoxy group, linked to the carbon atom in the15-position may be either in the α-configuration ##STR5## or in theβ-configuration ##STR6## When on the carbon atom in the 16-positionthere is a C₁ -C₄ alkyl group, said substituent may be either a16S-alkyl (α-configuration) or a 16R-alkyl (β-configuration) or a16(S,R)-alkyl, i.e. the mixture of the two 16S- and16R-diastereoisomers.

It is also evident that when the symbol represents a double bond andtherefore R₃ is a hydrogen atom, this hydrogen atom, being linked to acarbon atom which is no more asymmetric, may be obviously in an only onefixed position, i.e. on the plane of the ring, and therefore it may beneither in the α-position (i.e. below the plane of the ring) nor in theβ-position (i.e. above the plane of the ring).

The alkyl and alkoxy groups may be branched or straight chain groups.When R_(a) is a C₁ -C₁₂ alkyl, it is preferably methyl, ethyl or heptyl;n is preferably 1, m₁ is preferably 1 and m₂ is preferably zero. Whenone of R₁ and R₂ is acyloxy, it is preferably a C₂ -C₆ alkanoyloxygroup, e.g. acetoxy and propionyloxy, or a benzoyloxy group. When R is aC₁ -C₆ trihaloalkyl group, it is preferably trifluoromethyl.

When R is ##STR7## wherein R_(d) and/or R_(e) is a C₁ -C₆ aliphaticacyl, the aliphatic acyl group is preferably C₂ -C₆ alkanoyl.

When one of R₄ and R₅ is C₁ -C₆ alkoxy, it is preferably C₁ -C₃ alkoxy,in particular methoxy.

When one of R₄ and R₅ is aralkoxy, in the aralkoxy group the alkoxy ispreferably a C₁ -C₆ alkoxy and the aryl is preferably phenyl. Inparticular, when one of R₄ and R₅ is aralkoxy, it is preferablybenzyloxy. R₆ is preferably hydrogen.

When R₆ is C₁ -C₄ alkyl, the alkyl group is preferably methyl.

Examples of cations of pharmaceutically or veterinarily acceptable basesare either metallic cations or organic amine cations.

Particularly preferred metallic cations are those deriving from alkalinebases, e.g. lithium, sodium and potassium, and from earth-alkalinebases, e.g. magnesium and calcium, although also metallic cationsderiving from other bases, e.g. aluminium, zinc and iron, are comprisedin the scope of the invention.

Examples of cations deriving from organic amines are those deriving frommethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,N-methylhexylamine, decylamine, dodecylamine, allylamine,cyclopentylamine, cyclohexylamine, benzylamine, dibenzylamine,α-phenyl-ethylamine, β-phenyl-ethylamine, ethylenediamine,diethylenetriamine, morpholine, piperidine, pyrrolidine, piperazine, aswell as the alkyl derivatives of the latter four bases, mono-, di- andtri-ethanolamine, ethyl-diethanolamine, N-butyl-ethanolamine,2-amino-1-butanol, 2-amino-2-methyl-1-propanol, N-phenyl-ethanolamine,galactamine, N-methyl-glucamine, N-methyl-glucosamine, ephedrine,procaine, lysine and dehydroabietilamine.

The nor-compounds are those wherein n, or respectively m₁, are 3; thedinor-compounds are those wherein n, or respectively m₁, are 2; thetrinor-compounds are those wherein n, or respectively m₁, are 1; thetetranor-compounds are those wherein n, or respectively m₁, are zero.

Examples of preferred compounds of the invention are the following:

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(3'-trifluoromethyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9β,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-9α-benzoate;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-cyclohexyl-prost-5-en-13-ynoicacid-9α-propionate;

5c-9α,11α,15S-trihydroxy-20,19-dinor-18-phenyl-prost-5-en-13-ynoic acid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoic acid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(2'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(2'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid, as well the salts and the lower alkyl esters thereof.

The compounds of the invention are prepared by a process comprisingreacting an optically active compound, or a racemic mixture ofcompounds, of formula (II) ##STR8## wherein B,R₆ and R are as definedabove, D is --C.tbd.C-- or --CH═CX--, wherein X is bromine, chlorine oriodine, Y is hydroxy or a known protecting group bound to the ring by anethereal oxygen atom, and one of R'₄ and R'₅ is hydrogen and the otheris hydroxy, C₁ -C₆ alkoxy, aralkoxy, or a known protecting group boundto the chain by an ethereal oxygen atom, with a Wittig reagentcomprising a group of formula --(CH₂)₄ --A', wherein A' is a memberselected from the group consisting of (a") --CH₂ Z, wherein Z is hydroxyor a known protecting group bound to the chain by an ethereal oxygenatom; (b") --COOR'_(a), wherein R'_(a) is a hydrogen atom or a C₁ -C₁₂alkyl group; ##STR9## wherein R_(b) and R_(c) are as defined above, togive a compound of formula (III) ##STR10## wherein, A', Y, R'₄, R'₅, R₆,B and R are as defined above, which, when Z, if present, and Y are knownprotecting groups as defined above, and one of R'₄ and R'₅ is C₁ -C₆alkoxy, aralkoxy or a known protecting group as defined above and theother is hydrogen, may be optionally esterified to give the 9α- or9β-acyloxy derivative, and then, after optional selective saponificationof the 9β-acyloxy derivative to give the 9β-hydroxy derivative, removingthe known protecting groups in a compound of formula (III), wherein Z,if present, and Y are known protecting groups as defined above and/orone of R'₄ and R'₅ is a known protecting group as defined above and theother is hydrogen, or removing the known protecting groups as definedabove in the 9α- or 9β-acyloxy derivative of the compound of formula(III), so obtaining a compound of formula (I), wherein R₃ is hydroxy,the symbol is a single bond, one of R₁ and R₂ is hydrogen and the otheris hydroxy or acyloxy, and one of R₄ and R₅ is hydroxy, C₁ -C₆ alkoxy oraralkoxy and the other is hydrogen, or, if desired, oxidizing the 9α- or9β-hydroxy group in a compound of formula (IV) ##STR11## wherein A', R₆,B and R are as defined above, one of R'₁ and R'₂ is hydrogen and theother is hydroxy, Z, if present, and Y' are known protecting groups asdefined above, one of R"₄ and R"₅ is hydrogen and the other is C₁ -C₆alkoxy, aralkoxy or a known protecting group as defined above, to give acompound of formula (V) ##STR12## wherein A', Y', R"₄, R"₅, R₆, B and Rare as defined above, which, in turn, is subjected to the removal of theprotecting groups, to give, according to the reaction conditions used,either a compound of formula (I), wherein the symbol is a single bond,R₃ is hydroxy and R₁ and R₂, taken together, form an oxo group, or acompound of formula (I), wherein the symbol is a double bond, R₃ ishydrogen, and R₁ and R₂ together form an oxo group, and/or, if desired,converting a compound of formula (I), wherein one of R₄ and R₅ ishydrogen and the other is hydroxy, and wherein the hydroxy groups in the1- and/or 9- and/or 11-positions, when present, are protected asdescribed above, into a compound of formula (I) wherein one of R₄ and R₅is hydrogen and the other is C₁ -C₆ alkoxy or aralkoxy, and thenremoving, if present, the protecting groups, and/or, if desired,reacting a compound of formula (I), wherein A is --COOR_(a), whereinR_(a) is hydrogen, and the hydroxy groups in the 1-, 9-, 11- and/or15-positions are optionally protected as described above, with a base,followed, if required, by removal of the protecting groups, to give acompound of formula (I) wherein A is --COOR_(a), wherein R_(a) is acation of a pharmaceutically or veterinarily acceptable base, oresterifying a compound of formula (I), wherein A is --COOR_(a), whereinR_(a) is hydrogen and the hydroxy groups in the 1-, 9-, 11- and/or15-positions are optionally protected as described above, followed, ifrequired, by removal of the protecting groups, to give a compound offormula (I), wherein A is --COOR_(a), wherein R_(a) is C₁ -C₁₂ alkyl, orhydrolysing a compound of formula (I), wherein A is --COOR_(a), whereinR_(a) is C₁ -C₁₂ alkyl and the hydroxy groups in the 1-, 9-, 11- and/or15-positions are optionally protected as described above, followed, ifrequired, by removal of the protecting groups, to give a compound offormula (I), wherein A is --COOR_(a), wherein R_(a) is hydrogen, orreacting a compound of formula (I), wherein A is --COOR_(a), whereinR_(a) is hydrogen or C₁ -C₁₂ alkyl and the hydroxy groups in the 1-, 9-,11- and/or 15-positions are optionally protected as described above,with a compound of formula ##STR13## wherein R_(b) and R_(c) are asdefined above, followed, if required, by removal of the protectinggroups, to give a compound of formula (I), wherein A is ##STR14##wherein R_(b) and R_(c) are as defined above.

The known protecting groups (i.e. ether groups) should be convertible tohydroxy groups under mild reaction conditions, e.g. acid hydrolysis.Examples are acetalic ethers, enolethers and sylylethers. The preferredgroups are ##STR15## wherein W is --O-- or --CH₂ --, and Alk is a loweralkyl group. When in the lactol of formula (II) D is --C.tbd.C-- or--CH═CX--, wherein X is bromine or iodine, the Wittig reaction may beperformed using about two moles of Wittig reagent per mole of lactol andit is sufficient that the reaction lasts 10-20 minutes. When in thelactol of formula (II) D is --CH═CX--, wherein X is chlorine, it isnecessary, by using for example 1.5 to 2.5 moles of Wittig reagent permole of lactol, to prolong the reaction time up to ten hours or, if itis desired to use shorter reaction times, it is necessary to employ agreat excess of Wittig reagent (at least 5 moles of Wittig reagent permole of lactol for reaction times of about 30 minutes). Therefore, whenin the lactol of formula (II) D is --CH═CX--, X is preferably bromine oriodine.

When in the lactol of formula (II) D is --CH═CX--, wherein X is bromine,chlorine or iodine, the hydrogen atom linked to the carbon atom in the13- position and the halogen atom linked to the carbon atom in the 14-position may be either in the trans-position (geometric trans-isomers)or in the cis-position (geometric cis-isomers). Preferably they are inthe trans-position.

The Wittig reaction is performed by using the conditions generallyfollowed for this kind of reaction, i.e. in an organic solvent, forexample diethylether, hexane, dimethylsulphoxide, tetrahydrofuran,dimethylformamide or hexamethylphosphoramide, in presence of a base,preferably sodium hydride and potassium tert.butoxide, at 0° C. to thereflux temperature of the reaction mixture, preferably at roomtemperature or below.

The term "Wittig reagent" includes compounds of general formula

    (R.sub.a).sub.3 --P.sup.(+) --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --A' Hal.sup.(-)

wherein R_(a) is aryl or alkyl, Hal is halogen, e.g. bromine or chlorineand A' is as defined above. When R_(a) is aryl, it is preferably phenyl.When R_(a) is alkyl, it is preferably ethyl.

The preparation of the Wittig reagent is discussed in detail by Tripett,Quart. Rev., 1963, XVII, No. 4, 406.

When in the lactol of formula (II) D is --CH═CX--, wherein X is bromine,chlorine or iodine, during the reaction with the Wittig reagent, thedehydrohalogenation takes place as easily when the hydrogen atom linkedto the carbon atom in the 13- position and the halogen atom linked tothe carbon atom in the 14- position are in the trans-position as whenthey are in the cis-position.

The optional acylation of the 9α- hydroxy group in the compound offormula (III) may be performed in a conventional manner, for example bytreatment with an anhydride or a halide, e.g. a chloride of a carboxylicacid in presence of a base. In this case, a 9α- acyloxy derivative isobtained.

On the contrary, when the acylation of the 9α- hydroxy group in thecompound of formula (III) is carried out with a carboxylic acid inpresence of a compound of formula M^(v) Y₃, wherein M^(v) is a metalloidof the V group and Y is an alkyl, a dialkylamino or an aryl group, andof a hydrogen-acceptor agent, a 9β- acyloxy derivative is obtained, thatis, in the latter case, the esterification involves the completeinversion of configuration of the hydroxy group in the 9- position. Thisreaction is preferably carried out at room temperature in an inertanhydrous solvent, preferably selected from the group consisting ofaromatic hydrocarbons, such as benzene and toluene, linear or cyclicethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran anddioxan.

All the used reagents, that are the compounds of formula M^(v) Y₃, theesterifying carboxylic acid and the hydrogen-acceptor agent, arepreferably employed in the proportion of at least 1.5 mole per each moleof alcohol; 2 to 4 moles of the reagents per each mole of alcohol arepreferably used.

In the compound of formula M^(v) Y₃, M^(v) is preferably P, As, Sb,especially P. Again in the same compound, when Y is alkyl, it ispreferably methyl, while when Y is aryl, it is preferably phenyl; when Yis dialkylamino, it is preferably dimethylamino. The compound of formulaM^(v) Y₃ is preferably selected from the group consisting oftriphenylphosphine, triphenylarsine, triphenylstibine andhexamethyltriaminophosphine of formula [(CH₃)₂ N]₃ P.

The hydrogen-acceptor used is preferably an ester or an amide of theazodicarboxylic acid, preferably ethyl azodicarboxylate, but also otherhydrogen-acceptors may be used, for instance2,3,5,6-tetrachloro-benzoquinone, 2,3-dicyano-5,6-dichloro-benzoquinoneor azobisformamide.

The optional saponification of the 9β-acyloxy derivative to give thecorresponding 9β-hydroxy derivative may be effected in a conventionalway, e.g. by treatment with sodium or potassium hydroxide in an aqueousor alcoholic/aqueous solution, so obtaining also the saponification ofthe eventually present ester group in the 1-position. If it is desiredto saponify one of the 9β-acyloxy group to give the corresponding9β-hydroxy derivative, it is preferable to carry out the saponificationby treatment with a dry base, e.g. potassium or sodium carbonate, in adry alcohol, e.g. a lower aliphatic alcohol, such as methanol.

The removal of the known protecting groups bound to the ring, orrespectively to the chain, by an ethereal oxygen atom is, wheneverrequired, performed under conditions of mild acid hydrolysis, forexample with a mono- or poly-carboxylic acid, e.g. formic, acetic,oxalic, citric and tartaric acid, and in a solvent, for example, water,acetone, tetrahydrofuran, dimethoxyethane and lower aliphatic alcoholsor with a sulfonic acid, e.g. p-toluene-sulfonic acid in a solvent suchas a lower aliphatic alcohol, e.g. in dry methanol or in dry ethanol orwith a polystyrenesulfonic resin. For example, 0.1 to 0.25 Npoly-carboxylic acid (e.g. oxalic or citric acid) is used in thepresence of a convenient low boiling co-solvent which is miscible withwater and which can be easily removed in vacuo at the end of thereaction. The oxidation of the 9α- or 9β-hydroxy group to yield an oxogroup may be carried out with, for example, Jones reagent or Moffattreagent.

As stated above, the removal of the known protecting groups in acompound of formula (IV) may give, according to the reaction conditionsused, either a compound of formula (I), wherein the symbol is a singlebond, R₃ is hydroxy and R₁ and R₂, taken together, form an oxo group, ora compound of formula (I), wherein the symbol is a double bond, R₃ ishydrogen and R₁ and R₂, taken together, form an oxo group.

The former compound is obtained as the only product, by operating attemperatures ranging between about 25° C. and about 35°-38° C., while byoperating at higher temperatures, for example, at the reflux temperaturefor about 3 hours, the latter compound is obtained as the only product.The subsequent optional reactions, i.e. etherification of the 15-hydroxygroup, the salification, the esterification, the saponification and theconversion of an acid or an ester to an amide, may be carried out byconventional methods.

Thus, the etherification of the 15-hydroxy group may be carried out forexample by reaction with an optionally aryl-substituted diazoalkane inpresence of a catalyst such as fluoboric acid or boron trifluoride andin an organic solvent such as dichloromethane or by reaction of the freeor salified 15-hydroxy group with an alkyl or aralkyl halide in presenceof a base such as silver oxide and in a solvent such asdimethylsulphoxide and dimethylformamide.

For example, the saponification may be carried out as described above bytreatment with a base, such as an alkaline hydroxide, in an aqueous oralcoholic/aqueous solution, as well as the esterification may beperformed by treatment with an anhydride or a halide of an acid in thepresence of a base or by treatment with a diazoalkane. Thus, theconversion of a compound of formula (I), wherein A is --COOR_(a),wherein R_(a) is hydrogen into a compound of formula (I), wherein A is--CONR_(b) R_(c), wherein R_(b) and R_(c) are as defined above, may beeffected by treatment with an amine of formula NHR_(b) R_(c) in thepresence of a condensing agent, e.g. a carbodiimide such asdicyclohexylcarbodiimide and the conversion of a compound of formula(I), wherein A is --COOR_(a), wherein R_(a) is a C₁ -C₁₂ alkyl group,into a compound of formula (I), wherein A is --CONR_(B) R_(c), may beperformed, e.g., by treatment with an amine of formula NHR_(b) R_(c) ina suitable organic solvent at the reflux temperature for 2-3 hours.

The lactol of formula (II) may be prepared, in turn, by means of amulti-step process using as starting material an optically active orracemic lactone of formula (VI) ##STR16## wherein Y" is hydroxy, acyloxyor a known protecting group bound to the ring through an ethereal oxygenatom, X, R₆, B and R are as defined above, and wherein the hydrogen atomlinked to the carbon atom in the 13-position and the halogen atom linkedto the carbon atom in the 14-position (prostaglandin numbering) may beeither in the trans-position or in the cis-position. The multi-stepprocess to prepared the compound of general formula (II) starting fromthe lactone of formula (VI) involves the following steps:

(a) reduction of the 15-oxo-group (prostaglandin numbering) of thelactone of formula (VI) to yield a mixture of 15S- and 15R- ols havingthe formulae (VIIa) and (VIIb): ##STR17## wherein Y", X, R₆, B and R areas defined above, which, when Y" is different from hydroxy, areoptionally converted into the corresponding 15S-(C₁ -C₆)-alkoxy oraralkoxy derivatives, e.g., by treatment with a diazoalkane or byreaction with an alkyl or aralkyl halide in the presence of a hydrohalicacid acceptor, followed by the separation of the 15S-compound from the15R-compound, by the dehydrohalogenation of the separated compounds, togive a compound of formula (VIIIa) ##STR18## wherein R₄ is hydroxy, C₁-C₆ alkoxy or aralkoxy and Y", R₆, B and R are as defined above, or acompound of formula (VII Ib) ##STR19## wherein R₅ is hydroxy, C₁ -C₆alkoxy or aralkoxy and Y", R₆, B and R are as defined above.

If desired, the reduction may follow the dehydrohalogenation. Thereduction of the 15-oxo-group may be suitably performed in an organicsolvent, such as acetone, diethyl ether, dimethoxyethane, dioxane, orbenzene or their mixtures, by using, e.g. metal borohydrides, inparticular sodium borohydride, lithium borohydride, zinc borohydride andsodium trimethoxy-borohydride.

When the etherification of the 15 (S or R)-hydroxy group is carried outby treatment with a diazoalkane, the solvent used is preferably ahalogenated hydrocarbon and the reaction is preferably performed in thepresence of a catalyst such as borotrifluoride or tetrafluoboric acid(e.g. 0.01 equivalents) with an excess of the diazoalkane. When theetherification is carried out by reaction with an alkyl or aralkylhalide, the solvents used are preferably dimethylsulphoxide,hexamethylphosphoramide, dimethylformamide and the acceptor of theformed hydrohalic acid is a base selected e.g. from the group consistingof barium oxide and silver oxide and an excess of halide is employed.The separation of the 15S-compound from the 15R-compound may beperformed by chromatography, e.g. silica gel chromatography, or byfractionated crystallization.

The dehydrohalogenation may be performed in a solvent which ispreferably selected from the group consisting of dimethylsulphoxide,dimethylformamide and hexamethylphosphoramide in the presence of a basewhich may be for example an alkaline metal amide, potassium t.butoxideor the anion CH₃ --SO--CH₂.sup.(-).

(b) Optional conversion of a compound of formula (IX) ##STR20## whereinY", D, R₄, R₅, R₆ B and R are as defined above, into a compound offormula (X) ##STR21## wherein D, R₆, B and R are as defined above, Y' isa known protecting group bound to the ring through an ethereal oxygenatom and one of R₄ '" and R₅ '" is a known protecting group bound to thechain by an ethereal oxygen atom and the other is hydrogen.

This conversion is preceded, when in the compound of formula (VIII) Y"is an acyloxy group, by saponification for example by mild treatmentwith an alkali, to give a compound of formula (VIII) wherein Y" ishydroxy.

The conversion of a comound of formula (IX) into a compound of formula(X), i.e. the protection of the hydroxy groups in the 11- and/or15-position by a known protecting group as defined above, is preferablycarried out by reaction with an acetalic ether or a vinylic ether, e.g.of formula ##STR22## wherein W is --O-- or --CH₂ --, in the presence ofcatalytic amounts of e.g. phosphorus oxychloride, p-toluenesulphonicacid or benzenesulphonic acid or with a silyl ether, for instance, byreacting a trisubstituted chlorosilane in the presence of an acceptorbase (for example a trialkylamine) of the hydrohalic acid formed or withan enol ether, for instance by reaction, in the presence of an acidcatalyst, with a 1,1-dialkoxy-cyclopentane or cyclohexane, at the refluxtemperature in an inert solvent and then distilling the alcohol formedto obtain mixed dialkoxy ethers or enol ethers, according to the amountof catalyst used or the heating time.

(c) Reduction of a compound of formula (XI) ##STR23## wherein D, B, R'₄,R'₅, R₆, R and Y are as defined above, to give the lactol of formula(II).

The reduction may be performed by treatment with diisobutylaluminiumhydride or sodium bis-(2-methoxyethoxy)-aluminium hydride in an inertsolvent, for example, toluene, n-heptane, n-hexane or benzene or theirmixtures, at below 30° C. All the compounds mentioned under items (a),(b) and (c), may be either optically active compounds or racemicmixtures thereof.

The lactone of formula (VI) may be in turn prepared in an only one stepby reaction of an aldehyde of formula (XII) ##STR24## wherein Y" is asdefined above, with a halo-phosphonate carbanion of formula (XIII)##STR25## wherein R_(p) is lower alkyl and X, R₆, B and R are as definedabove.

The reaction is suitably performed in a solvent which is preferably drybenzene, dimethoxyethane, tetrahydrofuran, dimethylformamide or theirmixtures, and using a suspension of 1.1-1.2 molar equivalent of thehalo-phosphonate carbanion.

When in the aldehyde of formula (XII) Y" is an acyloxy group, it may befor example, acetoxy, propionyloxy, benzoyloxy and p-phenyl-benzoyloxy.When Y" is a known protecting group bound to the ring through anethereal oxygen atom, it may be for example one of the etherealprotecting groups reported here-above. The aldehyde of formula (XII) maybe prepared substantially as described by E. J. Corey at al., Ann. ofNew York Acad. of Sciences, 180, 24 (1971).

The halo-phosphonate carbanion of formula (XIII) may be in turn preparedby reacting a halo-phosphonate of formula (XIV) ##STR26## wherein R_(p),X, R₆, B and R are as defined above, with an equivalent of a basepreferably selected from the group consisting of sodium hydride, lithiumhydride, calcium hydride, an alkyl-lithium derivative and the anion CH₃--SO--CH₂.sup.(-).

The halo-phosphonate of formula (XIV) may be obtained by halogenation ofa phosphonate of formula (XV) ##STR27## wherein R_(p), B, R₆, and R areas defined above.

The halogenation may be carried out in a conventional manner, operatingsubstantially as in the halogenation of β-ketoesters.

The phosphonate of formula (XV) may be prepared by known methods, e.g.according to E. J. Corey et al., J. Am. Chem. Soc. 90, 3247 (1968) andE. J. Corey and G. K. Kwiatkowsky, J. Am. Chem. Soc., 88, 5654 (1966).Preferably the phosphonate of formula (XV) is prepared by reaction oflithium methylphosphonate with a lower alkyl ester of the acid offormula ##STR28## wherein R, B and R₆ are as defined above.

When this acid contains asymmetric carbon atoms, it is possible to useeither the racemic acid or one of its optical antipodes. Also thehalides of the above acid, e.g. the chlorides, may be used in thereaction with lithium methylphosphonate.

The above mentioned acid as well as its lower alkyl esters and itshalides, is a known compound or may be prepared by known methods.

For example β-phenyl-propionic acid and β-phenyl-α-alkyl-propionic aicdsmay be prepared starting from a benzyl halide or a substituted benzylhalide by malonic synthesis; phenoxy-aliphatic acids may be obtained byetherification of an optionally substituted phenol by reaction with ahalo-substituted aliphatic acid; benzyloxy-aliphatic acids may beprepared by etherification of the hydroxy groups of an hydroxy-aliphaticacid by reaction e.g. with a benzyl halide.

Alternatively, the halo-phosphonate carbanion of formula (XIII) may beprepared by reacting a phosphonate carbanion of formula (XVI) ##STR29##wherein R_(p), B, R₆ and R are as defined above, with a halogenatingagent selected from the group consisting of Br₂,pyrrolidone-hydrotribromide (PHTB), dioxandibromide, N-chloroacetamide,N-chlorosuccinimide, N-bromosuccinimide, N-bromoacetamide,N-bromocaprolactame, N-iodosuccinimide.

By using the imides as halogenating agents, the carbanion of thehalo-phosphonate of formula (XIII) is obtained directly with the use ofonly one equivalent of base; otherwise, it should be necessary to useanother equivalent of a base to obtain the carbanion of thehalo-phosphonate.

The phosphonate carbanion of formula (XVI) may be in turn obtained bythe treatment of the phosphonate of formula (XV) with an equivalent of abase, e.g. sodium, lithium or calcium hydride.

The halo-lactone of formula (VI) wherein X is bromine, may also beobtained by a multi-step process starting from a lactone of formula(XVII) ##STR30## wherein Y", B, R₆ and R are as defined above, which maybe prepared substantially as described by E. J. Corey et al., Annals ofNew York Acad. of Science, 180, 24 (1971). This multi-step processinvolves the following steps:

(a') reduction of the lactone of formula (XVII) to give a mixture of the15S- and 15R-ols of formulae (XVIIIa) and (XVIIIb) ##STR31## wherein Y",B, R₆ and R are as defined above. The reduction may be performed in anorganic solvent, such as acetone, diethylether and dimethoxyethane, byusing, for example, sodium borohydride, zinc borohydride, and lithiumborohydride.

(b') halogenation of the mixture of the two 15R- and 15S-ols to give amixture of 13 ,14 -dibromoalcohols of formulae (XIXa) and (XIXb)##STR32## wherein Y', B, R₆ and R are as defined above.

The halogenation is carried out in an inert solvent, preferably selectedfrom the group consisting of halogenated solvent, e.g. dichloromethane,dichlorethane, CCl₄ and a linear or cyclic ether, e.g. tetrahydrofuran,dioxane, dimethoxyethane or their mixtures, using a molar equivalent ofhalogenating agent or an excess of the same agent, which may be, e.g.Br₂, dioxandibromide, pyrrolidone hydrotribromide.

(c') oxidation of the mixture of the 13 , 14 -dibromoalcohols to give a13 14 -dibromo-15-oxo-derivative of formula (XX) ##STR33## wherein Y",B, R₆ and R are as defined above.

The oxidation is carried out at a temperature ranging between -25° andthe room temperature, by using a dichloromethane solution of thepyridine-chromic anhydride complex or a sulphoric solution of chromicanhydride in acetone (Jones reagent), or a carbodiimide, working indimethylsulphoxide in presence of a suitable acid.

(d') dehydrohalogenation of the 13 ,14 -dibromo-15-oxo-derivative togive the halo-lactone of formula (VI) wherein X is bromine.

The dehydrohalogenation may be performed by using an organic base, forexample a tert.amine in an inert solvent, or alternatively by using aninorganic base, for example potassium acetate in a solvent such asmethanol, ethanol acetic acid and the like. A further alternativeprocess for the preparation of the halo lactone of formula (VI) whereinX is bromine, is the reaction of the lactone of formula (XVII), in anethereal anhydrous solvent such as tetrahydrofuran and dimethoxyethaneor in a halogenated hydrocarbons with a halogenating agent such asbromine, phenyltrimethylammoniumtribromide and in particularpyrrolidone-hydrotribromide (1.1-1.3 molar equivalent) to give directlythe 13 ,14 -dibromo-15-oxo-derivative of formula (XX) which is thendehydrohalogenated as above described, to give the halo-lactone offormula (VI), wherein X is bromine. When acetic acid is used as solvent,the reaction may be performed in one step without recovering theintermediate dibromo compounds of formula (XX) by treatment of thereaction mixture (after addition of bromine), with about 1.1-2.5 molarequivalent of anhydrous potassium carbonate.

Also in the alternative methods for the preparation of the halo-lactoneof formula (VI), all the compounds may be either optically activecompounds or racemic mixtures thereof. In the preparation of thehalo-lactone of formula (VI) according to the here-above describedmethods, both compounds wherein the hydrogen atom linked to the carbonatom in the 13- position and the halogen atom linked to the carbon atomin the 14- position (prostaglandin numbering) are in the trans-position(geometric trans-isomers) and compounds wherein said atoms are in thecis-position (geometric cis-isomers) are obtained.

The geometric trans-isomers are obtained in a far higher percentage(92-95%), while the geometric cis-isomers are obtained in a far lowerpercentage (5-8%).

The geometric trans-isomers of formula ##STR34## can be easilydistinguished from the geometric cis-isomers of formula ##STR35## inthat the H_(A) vinylic protons of the two isomers resonate at differentpositions and the coupling constants of the H_(A) vinylic proton withthe H_(B) proton are well different (respectively 9 Hz for thetrans-isomer and 10.2 Hz for the cis-isomer).

Anyway, both the trans-isomers and the cis-isomers are intermediates forthe synthesis of the 13,14-dehydro-prostaglandins of the invention.

The lactol of formula (II) wherein D is--C.tbd.C--may be also preparedby dehydrohalogenation of the lactol of formula (II) wherein Dis--CH═CX--, wherein X is bromine, chlorine or iodine. Thedehydrohalogenation may be carried out in an aprotic solvent preferablyselected from the group consisting of dimethylsulphoxide,dimethylformamide and hexamethylphosphoramide by treatment with a basepreferably selected from the group consisting of potassiumtert.butylate, an alkali metal amide and the anion CH₃--SO--CH₂.sup.(-).

Among the intermediates described in this specification, the followingare compounds of the invention:

(1) the halo-phosphonate carbanion of formula (XIII);

(2) the lactol of formula (II);

(3) the lactone of formula (XXI) ##STR36## wherein Y", D, R₆, B and Rare as defined above;

(4) a compound of formula (XXII) ##STR37## wherein Y", R₆, B and R areas defined above, and one of R₄ ^(IV) and R₅ ^(IV) is hydroxy and theother is hydrogen, or R₄ ^(IV) and R₅ ^(IV) together form an oxo group;

(5) a compound of formula (XXIII) ##STR38## wherein A', Y', R"₄, R"₅,R₆, B and R are as defined above, one of R₁ and R₂ is hydrogen and theother is hydroxy or acyloxy or R₁ and R₂ togehter form an oxo group.

All the intermediates mentioned under the foregoing points (1) to (5)are optically active or racemic compounds.

The compounds of formula (I) may be used for the same therapeuticalindications as natural prostaglandins, with respect to which, however,they offer the advantage of being no substrates for the enzyme15-prostaglandin dehydrogenase, which as is known, quickly inactivatesnatural prostaglandins, and, moreover, are characterized by a moreselective therapeutical action.

The compounds of formula (I) furthermore inhibit the use of naturalprostaglandins as substrate by the same enzyme. Using the15-hydroxy-prostaglandin-dehydrogenase drawn from human placenta, invitro tests carried out with for example13,14-dehydro-17-phenyl-20,19,18-trinor-PGF₂α (or5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid), showed that the inhibition becomes partially competitive withrespect to PGF₂α (K_(i) =130 μM).

Because of their biological responses, the compounds of the inventionare useful to study, prevent, control, or alleviate a wide variety ofdieases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals and zoological specimens, andin laboratory animals, for example mice, rats, rabbits and monkeys.

In particular the compounds of the invention have selective luteolytic,abortifacient and labor-inducing activity and extremely low undesiredgastro-intestinal effects.

The following Table shows the comparison of two compounds of the presentinvention, i.e. 13,14-dehydro-17-phenyl-20,19,18-trinor-PGF₂α and13,14-dehydro-15S-methoxy-17-phenyl-20,19,18-trinor-PGF₂α(5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid), with PGF₂α,13,14-dehydro-PGF₂α, and with the olefinic analogue5c,13t-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prosta-5,13-dienoicacid (or 17-phenyl-20,19,18-trinor-PGF₂α) in the following in vitrotests: guinea pig ileum test and rat uterus test. In the Table theconventional value of 1 was given to the activity of PGF₂α in bothtests.

                  TABLE                                                           ______________________________________                                                       Guinea                                                                        Pig          Rat                                               Compound       Ileum*       Uterus**                                          ______________________________________                                        PGF.sub.2α                                                                             1            1                                                 17-phenyl-20,19,18-                                                                          2.34         1.54                                              trinor-PGF.sub.2α                                                                      (1.47-3.72)  (0.73-3.23)                                       13,14-dehydro-PGF.sub.2α                                                               0.6          1.09                                                              (0.406-0.913)                                                                             (0.66-1.77)                                       13,14-dehydro-17-                                                                            0.6          22.74                                             phenyl-20,19,18-                                                                             (0.29-1.23)  (16.05-32.2)                                      trinor-PGF.sub.2α                                                       13,14-dehydro-15S-                                                            methoxy-17-phenyl-                                                                           0.05         4.4                                               20,19,18-trinor-                                                                             (0.01-0.17)  (3.12-6.21)                                       PGF.sub.2α                                                              ______________________________________                                         *In a 10 ml thermostatic bath held at 35° C., ilea of male guinea      pigs, under 0.5 g traction, were subjected to carbondioxide in a Tyrode       solution; the preparation was left for 30 minutes to stabilize before the     compounds were tested. The response was recorded using a isotonic frontal     lever, long enough to amplify the response 4.5 times.                         **In a 10 ml thermostatic bath held at 29° C., oestrogenized rat       uteri under 0.5 g traction were subjected to carbondioxide in a Dejalon       saline solution. The prepration was left to stabilize for 30 minutes          before the compounds were tested. Response was measured using a isotonic      frontal lever, long enough to amplify the response 4.5 times.            

From the comparison of the activities in the above in vitro tests it isevident that a remarkable increase of the action selectivity onmiometrium was obtained as well as a reduced effect on the muscle of thegastroenteric apparatus was recorded, that means, a reduction of thegastrointestinal side effects which are always present when naturalprostaglandins are administered.

Also the phenoxy derivatives, e.g.13,14-dehydro-16-m-trifluoromethylphenoxy-20,19,18,17-tetranor-PGF₂.alpha.(or5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-m-trifluoromethylphenoxy-prost-5-en-13-ynoicacid) and 13,14-dehydro-16-p-fluorophenoxy-20,19,18,17-tetranor-PGF₂α(or5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-p-fluorophenoxy-prost-5-en-13-ynoicacid), when compared with PGF₂α (to whose activity the conventionalvalue of 1 was given), show a very high activity in the rat uterus test,i.e. 3.86 (2.96-5.03) and, respectively, 1.91 (1.34-2.73) and a very lowactivity in the guinea pig ileum test: 0.50 (0.05-5) for both thecompounds.

The action selectivity of the compounds of the invention on themiometrium and on the reproductive apparatus is also proven by theremarkable increase of the luteolytic activity in the pregnant rat atthe 9th-10th day of pregnancy. In fact, if the conventional value 1 isgiven to the luteolytic activity of PGF₂α, the value of 100 at least isto be given to the luteolytic activity of13,14-dehydro-17-phenyl-20,19,18-trinor-PGF₂α, and the value of 200 tothe luteolytic activity of13,14-dehydro-16-p-fluorophenoxy-20,19,18,17-tetranor-PGF₂α.

Pharmaceutical compositions containing a solution of13,14-dehydro-17-phenyl-20,19,18-trinor-PGF₂α as sodium salt or13,14-dehydro-16-p-fluorophenoxy-20,19,18,17-tetranor-PGF₂α as sodiumsalt in an aqueous isotonic buffered (pH 7.5) medium at a concentrationof 0.5 mg/ml were tested as to their ability of synchronizing the estrumof mares, cows, heifers and sowes and in all cases very good resultswere obtained. After administration of 0.5-3 ml of the above solution itwas noted a pronounced downfall of the haematic levels of progesteronewhich indicates a high luteolytic activity.

Furthermore, the compounds of formula (I), and in particular the PGF₂αderivatives, e.g. 13,14-dehydro-17-phenyl-20,19,18-trinor-PGF₂α, own autero-kinetic, i.e. abortifacient and labor-inducing, activity higherthan that of the corresponding cycloalkyl derivatives, e.g.13,14-dehydro-17-cyclohexyl-20,19,18-trinor-PGF₂α, as shown by thefollowing test:

Female rabbits of the average weight of four kilograms, ovariectomizedone week before, were anesthetized with pentobarbital sodium (40 mg/kgi.v.) and then a catheter bearing a rubber balloon filled with water wasinserted into an uterine horn, through the vaginal opening, and uterinemotility was recorded by means of a pressure transducer (Statham P 23ID) connected to a Beckman R 411 recorder; the tested prostaglandinswere then administered intravenously, each animal serving for one dose,in order to avoid tachyphylaxis.

Dose-response curves were obtained for each compound: the PGF₂αcompounds of the invention, e.g.13,14-dehydro-17-phenyl-20,19,18-trinor-PGF₂α, resulted about 10 to 15times more potent than the corresponding cycloalkyl derivatives, e.g.13,14-dehydro-17-cyclohexyl-20,19,18-trinor-PGF₂α. The compounds of theinvention, and in particular the PGF₂α derivatives, are therefore usefulfor controlling the reproductive cycle in ovulating female mammals,including humans and animals such as cattle, monkeys, rats, rabbits,dogs and the like. For this purpose, the compounds of the invention areadministered during a span of time starting approximately at the time ofovulation and ending approximately at the time of menses or just priorto menses. Additionally, expulsion of an embryo or a fetus isaccomplished by administration of the compound during the first third ofthe normal mammalian gestation period.

The 9-oxo-derivatives (PGE analogues) of formula (I), when compared withPGE₂ according to the method described by H. Shay et al., Gastroenter.,26,906 (1954) are about 2 times more active as gastric antisecretoryagents than PGE₂ and therefore are useful to reduce and controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation and accelerating the healing of suchulcers already present in the gastrointestinal tract.

Moreover, the antisecretory activity of the 9-oxo-compounds of formula(I), wherein a lower alkyl, particularly a methyl, is present on thecarbon atom in the 16-position, is further increased of 2 times when thealkyl is a 16S-alkyl, and of 4 times when the alkyl is a 16R-alkyl.

The compounds of the invention may be administered, either to humans orto animals, in a variety of dosage forms, e.g. orally in the form oftablets, capsules or liquids; rectally in the form of suppositories,parenterally, subcutaneously or intramuscularly, with intravenousadministration being preferred in emergency situations; by inhalation inthe form of aerosols or solutions for nebulizers; in the form of sterileimplants for prolonged action; or intravaginally in the form e.g. ofbougies.

The pharmaceutical or veterinary compositions containing the compoundsof the invention are prepared in a conventional way and containconventional carriers and/or diluents.

For example, for intravenous injection or infusion, sterile aqueousisotonic solutions are preferred. For subcutaneous or intramuscularinjection, sterile solutions or suspensions in aqueous or non-aqueousmedia are used; for tissue implants, a sterile tablet or silicone rubbercapsule containing or impregnated with the substance is used.

Conventional carriers or diluents are for example water, gelatine,lactose, starches, magnesium stearate, talc, vegetable oils, celluloseand the like.

Doses in the range of about 0.01 to 5 mg per kg of body weight may beused 1 to 4 times a day, the exact dose depending on the age, weight andcondition of the subject to be treated and on the frequency and route ofadministration. For example, the compounds of the invention can beadministered by intravenous infusion of a sterile isotonic salinesolution at the rate of 0.01 to 10, preferably 0.05 to 1, μg/kg ofmammal body weight per minute.

The invention is illustrated by the following examples, wherein theabbreviations "THP", "DIOX", "DMSO", "THF", "DMF", "DIBA", and "Et₂ O"refer to tetrahydropyranyl, dioxanyl, dimethylsulphoxide,tetrahydrofuran, dimethylformamide, diisobutylaluminium hydride andethyl ether, respectively.

EXAMPLE 1

To a stirred solution of NaH (80% dispersion in mineral oil, 1.67 g) indry benzene (300 ml) was added a dimethyl(2-oxo-4-phenyl)-butyl-phosphonate (14.60 g) solution in dry benzene (30ml). After one hour the vigorously stirred mixture was cooled at 5°-8°C., treated with finely powdered N-bromo succinimide (9.28 g) and then,after 15 minutes, with a benzene (50 ml) solution of5β-formyl-2α,4α-dihydroxy-cyclopent-1-yl-aceticacid-γ-lactone-4-p-phenylbenzoate (12.9 g). The stirring was continuedfor 90 minutes, then the reaction mixture was treated with aqueous 20%NaH₂ PO₄ solution, the organic phase was separated, washed with waterand dried. After removal of solvents in vacuum, crystallization fromethyl/ether afforded5β(2'-bromo-3'-oxo-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (17.6 g), m.p. 134°-140° C. [α]_(D)=-103° [α]₃₆₅ =-462° (C=0.5%, CHCl₃). Starting from a 4-acetate, thecorresponding 4-acetate was obtained.

EXAMPLE 2

5β(3'-oxo-4'-(m-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl)-2.alpha.,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (5.05 g; m.p. 114°-115° C.) wasobtained starting from 5β-formyl-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (5.9 g) in THF (70 ml) by treatmentwith a suspension of sodium salt ofdimethyl-(2-oxo-3-(m-trifluoromethyl)-phenoxypropylphosphonate (7.12 g;NaH 80% 0.60 g) in THF (180 ml). A bromine (1.52 g) solution in aceticacid (5 ml) was added, dropwise, to a stirred solution of the abovementioned 3'-oxo-compound (4.95 g) in acetic acid (10 ml) to obtainpersistent feeble red colour, then the solution of crude, not isolated,5β-(1' ,2'-dibromo-3'-oxo-4'-(m-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl)-2.alpha.,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate was treated with anhydrous K₂ CO₃ (3.2g) and heated for 3 hours at 80° C. After cooling at room temperature aprecipitate of crystalline material was obtained. It was filtered anddissolved with methylene chloride. The organic phase was washed with 10%NaHCO₃ aqueous solution and water until neutral, affording by removal ofsolvent and crystallization (from ethyl ether):5β-(2'-bromo-3'-oxo-4'-(m-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl)-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate, m.p. 108°-110°.

EXAMPLE 3

5β-(3'-oxo-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (4.3 g, m.p. 127°-128° C. [α]_(D)=-135° [α]₃₆₅° =-595 (C=0.5% CHCl₃) was obtained by treatment of benzene(70 ml) solution of 5β-formyl-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (3.5 g) with a sodium salt suspensionin benzene (70 ml) of the phosphonate prepared starting from NaH (0.45g) (80% dispersion in mineral oil) anddimethyl-(2-oxo-4-phenyl)-butyl-phophonate (3.93 g). The reactionmixture was stirred for 90 minutes at room temperature, treated with anexcess of aqueous 20% NaH₂ PO₄ solution and then the organic phase wasseparated, washed until neutral, affording after cystallization frommethanol the α,β-unsaturated ketone.

EXAMPLE 4

Using in the procedure of Example 1 a phosphonate selected from thegroup consisting of:

dimethyl-[2-oxo-4-(4'-fluoro)-phenyl]-butyl-phosphonate;

dimethyl-(2-oxo-4-(3'-chloro)-phenyl)-butyl-phosphonate;

dimethyl-[2-oxo-4-(3'-trifluoromethyl)-phenyl]-butyl-phosphonate;

dimethyl-[2-oxo-4-(4'-methoxy)-phenyl]-butyl-phosphonate;

dimethyl-(2-oxo-3-phenyl)-propyl-phosphonate;

dimethyl-(2-oxo-5-phenyl)-pentyl-phosphonate;

dimethyl-(2-oxo-3S-methyl-4-phenyl)-butyl-phosphonate;

dimethyl-(2-oxo-3R-methyl-4-phenyl)-butyl-phosphonate;

dimethyl-(2-oxo-3S-methyl-3-phenoxy)-propyl-phosphonate;

dimethyl-(2-oxo-3R-methyl-3-phenoxy)-propyl-phosphonate;

dimethyl-(2-oxo-3-phenoxy)-propyl-phosphonate;

dimethyl-(2-oxo-3-benzyloxy)-propyl-phosphonate;

dimethyl-[2-oxo-3-(4'-methoxy)-phenoxy]-propyl-phosphonate;

dimethyl-[2-oxo-3-(3'-chloro)-phenoxy]-propyl-phosphonate;

dimethyl-[2-oxo-3-(4'-fluoro)-phenoxy]-propyl-phosphonate;

dimethyl-[2-oxo-3-(3'-trifluoromethyl)-phenoxy]-propyl-phosphonate,

the following 2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate derivatives were prepared:

5β-[2'-bromo-3'-oxo-5'-(4"-fluoro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-5'-(3"-chloro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-5'-(3"-trifluoromethyl)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-5'-(4"-methoxy)-phenyl-pent-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'-oxo-4'-phenyl-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-6'-phenyl-hex-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'R-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'S-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'R-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'-benzyloxy-but-1'-trans-1'-enyl)-;

5β-[2'-bromo-3'-oxo-4'-(4"-methoxy)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-4'-(3"-chloro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-.

EXAMPLE 5

Using in the procedure of Example 3 a dimethylphosphonate selected fromthe group consisting of:

dimethyl-[2-oxo-4-(4'-fluoro)-phenyl]-butyl-phosphonate;

dimethyl-(2-oxo-4-(3'-chloro)-phenyl)-butyl-phosphonate;

dimethyl-[2-oxo-4-(3'-trifluoromethyl)-phenyl]-butyl-phosphonate;

dimethyl-[2-oxo-4-(4'-methoxy)-phenyl]-butyl-phosphonate;

dimethyl-(2-oxo-3-phenyl)-propyl-phosphonate;

dimethyl-(2-oxo-5-phenyl)-pentyl-phosphonate;

dimethyl-(2-oxo-3S-methyl-4-phenyl)-butyl-phosphonate;

dimethyl-(2-oxo-3R-methyl-4-phenyl)-butyl-phosphonate;

dimethyl-(2-oxo-3S-methyl-3-phenoxy)-propyl-phosphonate;

dimethyl-(2-oxo-3R-methyl-3-phenoxy)-propyl-phosphonate;

dimethyl-(2-oxo-3-phenoxy)-propyl-phosphonate;

dimethyl-(2-oxo-3-benzyloxy)-propyl-phosphonate;

dimethyl-[2-oxo-3-(4'-methoxy)-phenoxy]-propyl-phosphonate;

dimethyl-[2-oxo-3-(3'-chloro)-phenoxy]-propyl-phosphonate;

dimethyl-[2-oxo-3-(4'-fluoro)-phenoxy]-propyl-phosphonate;

dimethyl-[2-oxo-3-(3'-trifluoromethyl)-phenoxy]-propyl-phosphonate,

the following 2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate derivatives were obtained:

5β-[3'-oxo-5'-(4"-fluoro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[3'-oxo-5'-(3"-chloro)-phenyl-pent-1'trans-14-enyl]-;

5β-[3'-oxo-5'-(3"-trifluoromethyl)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[3'-oxo-5'-(4"-methoxy)-phenyl-pent-1'-trans-1'-enyl]-;

5β-(3'-oxo-4'-phenyl-but-1'-trans-1'-enyl)-;

5β-(3'-oxo-6'-phenyl-hex-1'-trans-1'-enyl)-;

5β-(3'-oxo-4'S-methyl-5'-phenyl-pent-1'trans-1'-enyl)-;

5β-(3'-oxo--4'R-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(3'-oxo-4'S-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(3'-oxo-4'R-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(3'-oxo-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(3'-oxo-4'-benzyloxy-but-1'-trans-1'-enyl)-;

5β-[3'-oxo-4'-(4"-methoxy)-phenoxy--but-1'-trans-1'-enyl]-;

5β-[3'-oxo-4'-(3"-chloro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[3'-oxo-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[3'-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-;

each of these compounds was reacted with bromine in acetic acid and thendehydrohalogenated with anhydrous potassium carbonate using theprocedure of Example 2 to obtain the following:

2α,4α-dihydroxy-cyclopentane-1α-acetic acid-γ-lactone-4-p-phenylbenzoatederivatives

5β-[2'-bromo-3'-oxo-5'-(4"-fluoro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-5'-(3"-chloro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-5'-(3"-trifluoromethyl)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-5'-(4"-methoxy)-phenyl-pent-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'-oxo-4'-phenyl-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-6'-phenyl-hex-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'R-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'S-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'R-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-oxo-4'-benzyloxy-but-1'trans-1'-enyl)-;

5β-[2'-bromo-3'-oxo-4'(4"-methoxy)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-4'-(3"-chloro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-4'-)4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'-oxo-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-;

EXAMPLE 6

3% bromine solution (30 ml) in carbon tetrachloride was added to asolution of5β-(3'-oxo-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate in carbon tetrachloride (150 ml).After discoloration, the reaction mixture was treated with pyridine (10ml) and stirred at room temperature for 10 hours.

The organic layer was washed with 4N aqueous sulfuric acid and wateruntil neutral, dried and then the solvents were evaporated in vacuum.The residue was crystallized from ethyl ether to afford5β-(2'-bromo-3'-oxo-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate, m.p. 139°-140° C.

EXAMPLE 7

To a solution of 2.5 g of5β-(3'-oxo-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate in dry THF (50 ml) was addedpyrrolidone-hydrotribromide (3 g) and the mixture was stirred for 3hours at room temperature. After dilution with ethyl ether (2 vol. theprecipitate was filtered and washed with ethyl ether. The filtrates werecollected, washed with aqueous 40% (NH₄)₂ SO₄ solution until neutral,dried and evaporated to dryness in vacuum. The crude 1' ,2' -dibromoderivative (14 g) so obtained was dissolved in dry benzene (25 ml) andtreated with 1.6 ml of pyridine for 12 hours at room temperature.

The benzenic layer was washed with aqueous 4N H₂ SO₄, aqueous 10% NaHCO₃and water until neutral and evaporated to dryness. After filtration onsilica gel (50 g) using as eluent methylene chloride-cyclohexane(80:20),one obtained 3.8 g of pure5β-[2'-bromo-3'-oxo-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-2.alpha.,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate.

EXAMPLE 8

A solution of dimethyl-[2-oxo-4-(4'-fluoro)-phenoxy]-butyl-phosphonate(0.79 g) in dry benzene (5 ml) was added dropwise to a suspension of NaH(80% dispersion in mineral oil, 72 mg) in dry benzene (8 ml) and themixture was stirred for one hour. After addition of N-chloro-succinimide(0.33 g) and further stirring for 30 minutes, the benzene solution wasfiltered and the so obtaineddimethyl-[1-chloro-2-oxo-4-(4'-fluoro)-phenoxy]-butyl-phosphonate wasadded to a suspension of NaH (80% dispersion in mineral oil, 72 mg) indry benzene. After 20 minutes,5β-formyl-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (0.7 g) in benzene (25 ml) was addedto the carbanion solution and the reaction mixture was stirred for 20minutes at room temperature. After addition of aqueous 50% NaH₂ PO₄solution, the organic layer was separated, washed with water untilneutral, evaporated to a small volume and the residue was absorbed onsilica gel (30 g). Elution with methylene chloride afforded 0.72 g of5β-[2'-chloro-3'-oxo-5'-(4"-fluoro)-phenoxy-pent-1'-trans-1'-enyl]-2.alpha.,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate.

EXAMPLE 9

Using in the procedure of Example 8, N-chloro-acetamide instead ofN-Cl-succinimide anddimethyl-[2-oxo-3-(4"-fluoro)-phenyl]-propyl-phosphonate to form thecarbanion, 0.71 g of5β-[2'-chloro-3-oxo-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-2.alpha.,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate were prepared.

EXAMPLE 10

A solution of5β-(2'-bromo-3'-oxo-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (51.5 g) in dimethoxyethane (150 ml)was added to a 0.07 M zinc borohydride solution in ethyl ether (3 l) andthe mixture was stirred for 3 hours. After destroying the excess reagentwith aqueous 2N sulfuric acid, the organic layer was separated, washedwith water until neutral and dried. The usual work-up afforded a crudemixture of the two 3'S and 3'R hydroxy epimers. Separation on silica gelcolumn (benzene: ethyl ether 80:20) yielded 27 g of5β-(2'-bromo-3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate, m.p. 102-104° C.[α]_(D) =-68.8°[α]₃₆₅ =-327.3 (C=0.5% CHCl₃) and 15 g of the 15'R-isomer m.p. 148-149°C.[α]_(D) =-82.2° [α]₃₆₅ =-403° (C=0.5%, CHCl₃).

EXAMPLE 11

Borontrifluoride ethereate(0.02 ml) was added to a solution of5β-(2'-bromo-3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (1.08 g) in methylene chloride, cooledat -10° C. and then the mixture was treated with an excess of adiazomethane solution in methylene chloride until a persistent yellowcolor.

The organic phase was heated to room temperature washed with aqueous 5%NaHCO₃ and with water until neutral, dried and evaporated to dryness.Crystallization from methanol afforded 1 g of 3'S-methoxy derivative,m.p. 126°-127° C.[α]_(D) =-77.5[α]₃₆₅ =-341° (C=0.5%, CHCl₃). Similarly,a solution, in methylene chloride, of the crude mixture of 3'S and3'R-alcohols (1.1 g), was treated with BF₃ etherate and diazomethane, asabove described. The resulting mixture of 3'S and 3'R-methoxy compounds(1.12 g) was chromatographed on silica gel (40 g) using benzene-ethylether 90:10 as eluent, so obtaining the 3'-S-methoxy derivative (0.6 g)and5β-(2'-bromo-3'R-methoxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (0.32 g), m.p. 115°-117° C.[α]_(D)=-68.3° [α]₃₆₄ =-348.4° (C=0.5%, CHCl₃).

EXAMPLE 12

A stirred solution of5β-[2'-chloro-3'-oxo-4'(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-2.alpha.,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (0.7 g) in methanol was cooled at-5°÷-8° C. and treated with NaBH₄ (58 mg). After 30 minutes the reactionof trans-enone was complete and the mixture was treated with anhydrousK₂ CO₃ (0.21 g) and stirred for additional two hours. The excess reagentwas destroyed by cautious addition of 15% aqueous acetic acid until pH6.5 and then the methanol was evaporated in vacuum. The residue waspartitioned between water and ethylacetate and the organic layer, afterthe usual work-up, was concentrated to a small volume and absorbed onsilica gel.

Elution with methylene chloride-ethyl ether 60:40 afforded 0.27 g of5β-[2'-chloro-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone and 0.145 g of 3'R-hydroxy-epimer. A solution of the3'S-alcohol in benzene was treated with 1,4-diox-2-ene andp-toluensulphonic acid (0.005 g) for 4 hours at room temperature.Pyridine (0.15 ml) was added and the solvents were evaporated in vacuumobtaining 0.42 g of the corresponding 3',4-bis-DIOX-ether.

EXAMPLE 13

The α-halo-α,β-unsaturated ketones, which had been prepared according tothe procedure of the Examples 1-9, were reduced using zincborohydride,as in the procedure of Example 10, or sodium borohydride, as in theprocedure of Example 12, affording a 4-ester, preferably a4-p-phenylbenzoate, of the following2α,4α-dihydroxy-cyclopentane-1α-acetic acid-γ-lactone derivatives:

5β-[2'-bromo-3'S-hydroxy-5'-(4"-fluoro)-phenyl-pent-1'-trans-1'-enyl]-

5β-[2'-bromo-3'S-hydroxy-5'-(3"-chloro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-5'-(3"-trifluoromethyl)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-5'-(4"-methoxy)-phenyl-pent-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'S-hydroxy-4'-phenyl-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-6'-phenyl-hex-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5α-(2'-bromo-3'S-hydroxy-4'S-methyl-4'-phenoxy-but-1!-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'R-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-phenoxy-but-1'trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-benzyloxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-(4"-methoxy)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

[α]_(D) =-70° [α]₃₆₅ =-315° (C=0.5%, CHCl₃);

5β-[2'-bromo-3'S-4'-(3"-chloro)-phenoxy-but-1'-trans-1'enyl]-;

5β-[2'-bromo-3'S-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-;

[α]_(D) =-62° [α]₃₆₅ =-285° (C=0.5%, CHCl₃);

5β-[2'-chloro-3'S-hydroxy-5'-(4"-fluoro)-phenoxy-pent-1'-trans-1'-enyl]-;

5β-[2'-chloro-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'R-hydroxy-5'-(4"-fluoro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'R-hydroxy-5'-(3"-chloro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'R-hydroxy-5'-(3"-trifluoromethyl)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'R-hydroxy-5'-(4"-methoxy)-phenyl-pent-1'-trans-1'-enyl];

5β-(2'-bromo-3'R-hydroxy-4'-phenyl-but-1'-enyl)-;

5β-(2'-bromo-3'-R-hydroxy-6'-phenyl-hex-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'R-hydroxy-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'R-hydroxy-4'S-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'R-hydroxy-4'R-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'R-hydroxy-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'R-hydroxy-4'-benzyloxy-but-1'-trans-1'-enyl)-;

5β-[2'-bromo-3'R-hydroxy-4'-(4"-methoxy)-phenoxy-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'R-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

[α9 _(D) =-72° [α]₃₆₅ =-315° (C=0.5%, CHCl₃);

5β-[2'-bromo-3'R-hydroxy-4'-(3"-chloro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'R-hydroxy-4"-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-;

[α]_(D) =-62° [α]₃₆₅ =-285° (C=0.5%, CHCl₃);

5β-[2'-chloro-3'R-hydroxy-5'-(4"-fluoro)-phenoxy-pent-1'-trans-1'-enyl]-;

5β-[2'-chloro-3'R-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

as a mixture of the two epimeric alcohols, which was chromatographicallyseparated on silica gel or used as such in the following Examples.

EXAMPLE 14

Using diazoethane in the procedure of Example 11,5β-(2'-bromo-3'S-ethoxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate was obtained.

EXAMPLE 15

A solution of5β-(2'-bromo-3'S-hydroxy-4'-phenoxy-but-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate, [α]_(D) -71° (C=0.5%, CHCl₃) (0.13 g)in dry dimethylformamide (5 ml) was stirred in the presence of bariumoxide (0.12 g) and benzyl bromide (0.1 g) for five days. Afterfiltration, the excess solvent was evaporated in vacuum and the residuewas partitioned between ethyl ether and water. The organic phase, afterthe usual work-up, was concentrated and absorbed on silica gel. Elutionwith benzene/ethyl ether (85:15) afforded 0.098 g of5β-(2'-bromo-3'S-benzyloxy-4'-phenoxy-but-1'-trans-1'-enyl)-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate.

EXAMPLE 16

A solution of5β-(2'-bromo-3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4-p-phenylbenzoate (2.72 g) in dry methanol (30 ml) wasstirred with 0.42 of anhydrous K₂ CO₃ at room temperature for 2-5 hours.

The mixture was then treated with aqueous NH₂ SO₄, until pH 5, themethanol was evaporated in vacuum and the residue was partitionedbetween ethyl ether and a phosphate buffer (pH 6.8). After evaporationof the solvent the residue was absorbed on silica gel (30 g) and elutedwith ethyl ether to remove methyl-p-phenylbenzoate and with ethylacetate to obtain5β-(2'-bromo-3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone, [α]_(D) =-12.7° [α]₃₆₅ =-47.5 (C=0.5% CHCl₃).

EXAMPLE 17

According to Example 16, selective saponification of the ester functionof the compounds prepared in the Examples 10-15, allowed to obtain thefollowing 2α,4α-dihydroxy-cyclopentane-1α-acetic acid-γ-lactonederivatives:

5β-[2'-bromo-3'S-hydroxy-5'-(4"-fluoro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-5'-(3"-chloro)-phenyl-pent-1'-trans-1'-enyl];

5β-[2'-bromo-3'S-hydroxy-5'-(3"-trifluoromethyl)-phenyl-pent-1'-trans-1'-enyl]-

5β-[2'-bromo-3'S-hydroxy-5'-(4")methoxy)-phenyl-pent-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'S-hydroxy-4'-phenyl-but-1'-trans-1'-enyl)-;

5β-(2'-bromo3'S-hydroxy-6'-phenyl-hex-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'S-hydroxy-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'S-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'R-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-benzyloxy-but-1'-trans-1'-enyl)-;

5β-[2'-bromo-3'S-hydroxy-4'-(4"-methoxy)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(3"-chloro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-chloro-3'S-hydroxy-5'-(4"-fluoro)-phenoxy-pent-1'-trans-1'-enyl]-;

5β-[2'-chloro-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'-S-hydroxy-5'-phenyl-pent-1'-trans-1'enyl)-;

5β-(2'-bromo-3'S-methyoxy-5'-phenyl-pent-1'-trans-1'enyl)-;

5β-(2'-bromo-3'S-ethoxy-5'-phenyl-pent-1'trans-1-enyl)-;

5β-(2'-bromo-3'S-methoxy-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-methoxy-4'R-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-benzyloxy-4'-phenoxy-but-1'-trans-1'-enyl)-;

as well as their 3'R-epimeric-derivatives.

EXAMPLE 18

A solution of 0.25 g of5β-[2'-bromo-3'S-hydroxy-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γlactone, [α]_(D) =-13.2° (C=0.5% CHCl₃) in methylene chloride (8ml) was treated with 2.3-dihydropyran (0.12 ml) and p-toluenesulfonicacid (7 mg). After 2 hours the mixture was washed with 10% aqueousNaHCO₃ and water until neutral. The organic solution was dried on Na₂SO₄ and the solvents were evaporated to obtain5β[2'-bromo-3'-S-hydroxy-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4,3'-bis-THP-ether (0.33 g ), [α]_(D) =-29.5° (C=1%CHCl₃).

Using this procedure, the 3',4-bis acetalic ethers (dioxanylethers,α-ethoxy-ethylethers and preferably 2"-tetrahydropyranylethers) of thefollowing 2α,4α-dihydroxy-cyclopentane-1α-acetic acid-γ-lactonederivatives were obtained:

5β-[2'-bromo-3'S-hydroxy-5'-(4"-fluoro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-5'-(3"-chloro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-5'-(3"-trifluoromethyl)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-5'-(4"-methoxy)-phenyl-pent-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'S-hydroxy-4'-phenyl-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-6'-phenyl-hex-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'S-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'R-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-benzyloxy-but-1'-trans-1'-enyl);

5β-[2'-bromo-3'S-hydroxy-4'-(4"-methoxy)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(3"-chloro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-chloro-3'S-hydroxy-5'-(4"-fluoro)-phenoxy-pent-1'-trans-1'-enyl]-;

5β-[2'-chloro-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-;

as well as their 3'R-epimeric-derivatives.

EXAMPLE 19

A solution of5β-(2'-bromo-3'S-methoxy-5-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone (4.4 g) in methylene chloride (50 ml) was treated with2,3-dihydropyran (1.3 ml) and p-toluensulfonic acid (20 mg). After 2hours the methylene chloride solution was washed with 10% aqueousNaHCO₃, with water and dried. The solvent was evaporated so obtaining5.34 g of the corresponding 4-THP-ether, [α]_(D) =-3.9° (C=1% CHCl₃).Analogously, starting from the 3 -alkoxy derivatives of the Example 17,by treatment with a vinyl ether (f.e. 2,3-dihydropyran, 1,4-diox-2-eneand α-ethoxy-vinyl ether), the 4-acetalic ethers(2"-1",4"-dioxanylethers, α-ethoxy-ethylethers and preferably2"-tetrahydropyranylethers) of the following2α,4α-dihydroxy-cyclopentane-1α-acetic acid-γ-lactone derivatives wereobtained:

5β-(2'-bromo-3'S-methoxy-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-methoxy-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-ethoxy-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-methoxy-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'-S-methoxy-4'R-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-benzyloxy-4'-phenoxy-but-1'-trans-1'-enyl)-;

as well as their 3'R-epimeric compounds.

EXAMPLE 20

A 0.5 M solution of DIBA in toluene (9.8 ml) was added over a 15 minutesperiod to a stirred solution of5β-[2'-bromo-3'S-hydroxy-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-3',4-bis-THP-ether (1.14 g) in toluene (20 ml) and cooledto -70° C.

After 30 minutes, the mixture was treated with 5 ml of 2M 2-propanolsolution in toluene, heated to room temperature and then aqueoussaturated NaH₂ PO₄ solution (5 ml) was added. The mixture was stirredfor 4 hours and, after addition of anhydrous Na₂ SO₄, filtered.

The solvent was evaporated to dryness affording 1.1 g of5β-[2'-bromo-3'S-hydroxy-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-2α,4α-dihydroxy-cyclopentane-1α-ethanal-γ-lactol-3',4-bis-THP-ether.

EXAMPLE 21

5β-(2'-bromo-3'S-methoxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-ethanal-γ-lactol-4-THP-ether0.65 g [α]_(D) =-4°,[α]₃₆₅ =-27.3° (C=1% CHCl₃) was obtained startingfrom a solution of the corresponding γ-lactone (0.8 g) in toluene (10ml) by reduction with 0.5 M DIBA in benzene (4.4 ml) working at -70° C.

EXAMPLE 22

Under a nitrogen atmosphere, a mixture of a 70% solution of sodiumbis-(2-methoxy-ethoxy)-aluminium hydride in benzene (0.58 ml) andtoluene (5 ml) was added to a stirred solution of5β-[2'-chloro-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'enyl]-2α,4α-dihydroxy-cyclopentane-1α-aceticacid-γ-lactone-4,3'-bis-DIOX-ether, cooled at -60° C. The stirring wascontinued for 3 hours and the excess reagent was destroyed by additionof acetone-toluene (1:1) 10 ml. The mixture was warmed at roomtemperature, treated with 2 ml of aqueous saturated NaH₂ PO₄ solutionand stirred for 4 hours. The precipitate was filtered out and theorganic solvents were evaporated to dryness affording 0.41 g of5β-[2'-chloro-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-2α,4α-dihydroxy-cyclopentane-1α-ethanal-γ-lactol-3',4-bis-DIOX-ether.

EXAMPLE 23

By reduction of a γ-lactone of the Examples 18 and 19, using as reducingagents DIBA, according to the procedure of Examples 20 and 21, or sodiumbis-(2-methoxy-ethoxy)-aluminium hydride, according to the procedure ofExample 22, the following2α,4α-dihydroxy-cyclopentane-1α-ethanal-γ-lactol derivatives:

5β-[2'-bromo-3'S-hydroxy-5'-(4"-fluoro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-5'-(3"-chloro)-phenyl-pent-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-5'-(3"-trifluoromethyl)-phenyl-pent-1'-trans-1'-enyl]-;

5β-2'-bromo-3'S-hydroxy-5'-(4"-methoxy)-phenyl-pent-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'S-hydroxy-4'-phenyl-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-6'-phenyl-hex-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'S-methyl-5'-phenyl-pent-1'trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'S-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'R-methyl-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-phenoxy-but-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-hydroxy-4'-benzyloxy-but-1'-trans-1'-enyl-)-;

5β-[2'-bromo-3'S-hydroxy-4'-(4"-methoxy)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(3"-chloro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-bromo-3'S-hydroxy-4'-(3"-trifluoromethyl)-phenoxy-but-1'-trans-1'-enyl]-;

5β-[2'-chloro-3'S-hydroxy-5'-(4"-fluoro)-phenoxy-pent-1'-trans-1'-enyl]-;

5β-[2'-chloro-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-;

5β-(2'-bromo-3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-,

were obtained as 3',4-bis-acetalic ethers (bis-DIOX-ethers;bis-α-ethoxyethyl ethers and preferably bis-THP-ethers) and thefollowing 2α,4α-dihydroxy-cyclopentane-1α-ethanal-γ-lactol derivatives:

5β-(2'-bromo-3'-S-methoxy-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-methoxy-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-ethoxy-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-methoxy-4'S-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-methoxy-4'R-methyl-5'-phenyl-pent-1'-trans-1'-enyl)-;

5β-(2'-bromo-3'S-benzyloxy-4'-phenoxy-but-1'-trans-1'-enyl)-,

were obtained as 4-acetalic ethers (DIOX-ethers, α-ethoxy-ethylethersand preferably THP-ethers).

EXAMPLE 24

5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-prost-5-en-13-ynoicacid-11-THP-ether (1.1 g), [α]_(D) =+11.6°[α]₃₆₅ =+13.2° (C=1% CHCl₃)was obtained by addition of a solution of 1.28 g of5β-(2'-bromo-3'S-methoxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-ethanal-γ-lactol-4-THP-etherin benzene (0.6 ml) and DMSO (1.5 ml) to a stirred solution of ylideprepared from triphenyl-(4-carboxybutyl)-phosphonium bromide (5.6 g) andpotassium tert-butoxide (3 g) in 12 ml of dry DMSO cooled at 20° C.

The mixture was stirred for 3 hours, diluted with water and extractedwith ethyl ether to remove the triphenylphosphine oxide. The etherealextracts were combined, back-washed with 0.5 N KOH and then discarded.

The alkaline washes were combined with the original alkaline phase,acidified to pH 4.9 and extracted several times with ethyl ether:pentane 1:1. These combined organic extracts were washed with saturated(NH₄)₂ SO₄ and evaporated to dryness affording the prostynoicderivative.

EXAMPLE 25

Under a nitrogen atmosphere, cooling the reaction mixture at 15°-20° C.,a solution of potassium tert-butoxide (5.03 g) in dry DMSO was added toa solution of 10.25 g of triphenyl-(4-carboxybutyl)-phosphonium bromideto obtain a deep red-yellow solution of the ylide in DMSO. To thisstirred solution (cooled to 15-17°), a solution of 2.06 g of5β-(2'-bromo-3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-ethanal-γ-lactol-3',4-bis-THP-etherin DMSO (10 ml) was added. After 4 hours, the mixture was diluted with0.5 N KOH (60 ml) and extracted with ethyl ether. These etherealextracts were washed with (2×5) 0.5 N KOH and water until neutral andthen discarded.

The aqueous alkaline phases were collected, acidified to pH 4.9 with 2NH₂ SO₄ and extracted with ethyl ether-pentane(1:1)obtaining, after usualwork-up, 1.92 g of5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-11,15-bis-THP-ether,[α]_(D) =+11.2 (CHCl₃). The methyl ester wasobtained by adding an ethereal solution of diazomethane to a solution ofthe acid until a persistent yellow colour. The solvent was evaporated invacuum so obtaining 0.8 g of methyl5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoate-11,15-bis-THP-ether.

EXAMPLE 26

Under a nitrogen atmosphere, NaH (80% in mineral oil, 1.49 g) suspensionin dry DMSO (40 ml) was heated at 60°-65° C. for 3 hours until no morehydrogen evolved; then the solution was cooled to 15°-17° and treatedwith a solution of triphenyl-(4-carboxybutyl)-phosphoniumbromide (10.9g) in DMSO, under vigorous stirring.

To the resulting deep red-orange solution, a solution of5β-[2'-chloro-3'S-hydroxy-4'-(4"-fluoro)-phenoxy-but-1'-trans-1'-enyl]-2α,4α-dihydroxy-cyclopentane-1α-ethanal-γ-lactol-3',4'-bis-DIOX-ether(1.71 g) in DMSO (10 ml) was added, cooling the reaction mixture to15°-20° C. After hours it was diluted with water (50 ml) and the aqueousmedium was extracted repeatedly with ethyl ether to removetriphenylphosphine.

These organic extracts were back-washed with 1 N NaOH, with water andthen discarded.

The combined aqueous phases were acidified to pH 4.4 with 2N sulfuricacid and extracted with ethyl ether: pentane (1:1; these organicextracts were combined, washed with aqueous saturated (NH₄)₂ SO₄ andthen evaporated to dryness to afford 1.52 g of5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid-11,15-bis-DIOX-ether.

EXAMPLE 27

Aγ-lactol, which had been prepared in the Examples 20-23, was reactedwith the ylide obtained by treatment of thetriphenyl-(4-carboxybutyl)-phosphonium bromide with potassiumtert-butoxide, according to the procedure of the Examples 24 and 25, orwith NaH--DMSO, according to the procedure of the Example 26, and thefollowing 11,15-bis-acetalic ethers (DIOX-ethers,α-ethoxyethyl ethersand preferably THP-ethers) were prepared:

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(3'-trifluoromethyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(4'-methoxy)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19-dinor-18-phenyl-prost-5-en-13-ynoic acid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-15S-trihydroxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-benzyloxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(3'-trifluoromethyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(4'-methoxy)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19-dinor-18-phenyl-prost-5-en-13-ynoic acid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-15R-trihydroxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-benzyloxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-(4'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

as well as the following 11-acetalic ethers (DIOX-ethers, α-ethoxy-ethylethers and preferably THP-ethers):

5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-ethoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5-9α,11α-dihydroxy-15S-methoxy-10,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-benzyloxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-ethoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-methoxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-methoxy-20,19,18-trinor-16R-methyl-17-phenyl-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-benzyloxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid.

Afterwards the free acids were converted into their alkyl esters bytreatment with a diazoalkane solution.

EXAMPLE 28

To a solution of triphenylphosphine (30 g) in dry acetonitrile,5-bromo-pentanoic acid-N,N-diethylamide (23.5 g) was added and themixture was refluxed for 16 hours. After cooling to room temperature,the crystalline product was filtered off to yield 34.2 g oftriphenyl-(4-N,N-diethylcarboxamide-butyl)-phosphoniuu bromide. Under anitrogen atmosphere, a solution of this compound (1.5 g) in DMSO wasadded to a stirred solution of sodium dimethylsulfoxide carbanion,cooled to 10°-14° C., which had been prepared by heating 115 mg NaH(80%) in 10 ml of DMSO at 60°-65° C. for 3 hours. Then the ylidesolution was treated with a solution of5β-(2'-bromo-3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-ethanol-γ-lactol-3',4-bis-THP-etherin dry DMSO (4 ml) (0.5 g) for 4 hours at room temperature. The mixturewas diluted with water (20 ml) and extracted with ethyl ether-pentane1:1. The combined ethereal extracts were washed until neutral,concentrated to small volume and the residue was absorbed on silica gel.Elution with benzene ethyl ether (85:15) afforded 0.42 g of5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-N,N-diethyl amide-11,15-bis-THP-ether.

A solution of this compound (0.15 g) in dry methanol (10 ml) was treatedwith p-toluensulfonic acid (8 mg) at room temperature for 2 hours.Pyridine (0.05 ml) was added. The solvent was evaporated in vacuum andthe residue was partitioned between water and ethyl ether. The organicextracts were collected, evaporated to dryness and after thin layerchromatography on silica gel, 72 mg of5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-N,N-diethylamide were obtained.

EXAMPLE 29

Triphenylphosphine (0.53 g), benzoic acid (0.24 g) and 5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoic acidmethylester-11,15-bis-THP-ether,[α]_(D) =+12° (CHCl₃), (0.45 g) were dissolvedin dry benzene (20 ml) and a solution of diethylazo-bis-carboxylate(0.35 g) in benzene (5 ml) was added dropwise to this mixture. After 20minutes, the organic layer was washed with aqueous 2N H₂ SO₄, water,aqueous 10% NaHCO₃ and water until neutral, dried and the solventsevaporated to dryness. The residue was absorbed on silica gel andelution with benzene-ethyl ether afforded 0.41 g of5c-9β,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid methyl ester-11,15-bis-THP-ether-9-benzoate.

A sample of this compound (0.14 g) was treated in dry methanol (4.5 ml)with anhydrous potassium carbonate (50 mg) for 3 hours at roomtemperature. The solvent was evaporated in vacuum and the crude productwas partitioned between aqueous 25% NaH₂ PO₄ solution and ethyl acetate.The organic phase was separated and after thin layer chromatography onsilica gel, 92 mg of5c-9β,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid methyl ester-11,15-bis-THP-ether were obtained. Analogously thefollowing 9-benzoate derivatives:

5c-9β,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid methyl ester-11,15-bis-THP-ether;5c-9β,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid methyl ester-11-THP-ether, were prepared and after selectivehydrolysis the corresponding free 9β-hydroxy compounds were prepared.

EXAMPLE 30

A stirred solution of5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-methyl ester-11-THP-ether (0.48 g) in acetone (15 ml) was cooled to-15÷-12° C. and treated with Jones reagent (1.4 ml). After 15 minutesthe mixture was diluted with benzene and washed repeatedly with aqueous30% (NH₄)₂ SO₄ solution until neutral. The solvent was evaporated invacuum to provide5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-methyl ester-11-THP-ether (0.37 g).

EXAMPLE 31

To a stirred solution of5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-11,15-bis-THP-ether (0.55 g) in acetone (15 ml), cooled to -14÷-10°C., Jones reagent (1.4 ml) was added. After 30 minutes, the mixture wasdiluted with benzene (50 ml) and washed until neautral with saturated(NH₄)₂ SO₄ solution. The combined aqueous fractions were extracted withbenzene and the organic phases were collected, dried on Na₂ SO₄,evaporated to dryness affording 0.48 g of5c-9-oxo-11α15S-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-11,15-bis-THP-ether.

EXAMPLE 32

Starting from 9-hydroxy-prost-13-ynoic derivatives either as free acidsor as their methyl esters, which were prepared in the Examples 24, 25,26, 27, 28 and 29, oxidation with Jones reagent afforded, either as freeacids or their methyl esters, the following 11,15-bis-THP-ethers:

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17(4'-fluoro)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihyroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-(3'-trifluoromethyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-(4'-methoxy)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19-dinor-18-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13ynoicacid;5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetramor-16-benzyloxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(4'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenyoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;

5c-9oxo-11α,15S-dihydroxy-20,19,18-trinoir-17-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenyl-prost-5-en-13-ynoicacid;

5c-9oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(3'-trifluoromethyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(4'-methoxy)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19-dinor-18phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-benzyloxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(4'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

as well as the following 11-THP-ethers:

5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-ethoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-benzyloxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9oxo-11α-hydroxy-15R-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9oxo-11α-hydroxy-15R-ethoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15R-methoxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15R-methoxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13ynoicacid;

5c-9oxo-11α-hydroxy-15R-benzyloxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

and the following compounds:

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid-11,15-bis-DIOX-ether;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-N,N-diethylamide-11,15-bis-THP-ether.

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid-11,15-bis-DIOX-ether;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoic-acid-N,N-diethylamide-11,15-bis-THP-ether.

EXAMPLE 33

A solution of5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-11-THP-ether (0.2 g) in acetone (7 ml) was heated at 40° for 12hours in the presence of 0.2N aqueous oxalic acid (5 ml). The acetonewas evaporated in vacuum, and the resulting emulsion was extracted withethyl ether. The organic extracts were washed until neutral with aqueoussaturated (NH₄)₂ SO₄, dried on Na₂ SO₄ and evaporated to dryness. Theresidue was chromatographed on acid washed silica gel, using CH₂ Cl₂-allyl acetate (80:20)as eluent, so obtaining 0.1 g of pure5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid[α]_(D) =-23.7° [α]₃₆₅ =-64° (C=0.5% EtOH). Using this procedure inthe deacetalization of the compounds of the Examples 30, 31 and 32, thefollowing 9-oxo-11α -hydroxy-prostanoic acids were obtained:

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-(3'-trifluoro-methyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-(4'-methoxy)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19-dinor-18-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-benzyloxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(4'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(3'-trifluoromethyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-(4'-methoxy)-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19-dinor-18-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-benzyloxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(4'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-ethoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-methoxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15S-benzyloxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15R-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15R-ethoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15R-methoxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15R-methoxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9-oxo-11α-hydroxy-15R-benzyloxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-N,N-diethylamide;

5c-9-oxo-11α,15R-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid.

EXAMPLE 34

A solution of5c-9-oxo-11α,15S-dihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-11,15-bis-THP-ether (0.55 g) in acetone (10 ml) was refluxed with 6ml of a 0.15 N aqueous oxalic acid for 6 hours.

The excess acetone was removed in vacuo and the solution was extractedwith ether. The organic extract was concentrated and absorbed onacid-washed silica gel. Elution with benzene ethyl ether afforded 0.18 gof5c-9-oxo-15S-hydroxy-20,19,18-trinor-17-phenyl-prost-5,10-dien-13-ynoicacid.

The methyl ester of this compound was obtained when deacetalization wasaccomplished in methanol (15 ml) in the presence of p-toluenesulfonicacid (30 mg).

Analogously, starting from the corresponding 9-oxo-11α-acetalic ether,the following compounds:

5c-9-oxo-15S-methoxy-20,19,18-trinor-17-phenyl-prosta-5,10-dien-13-ynoicacid;

5c-9-oxo-15S-hydroxy-20,19,18,17-tetranor-16-phenoxy-prosta-5,10-dien-13-ynoicacid were prepared.

EXAMPLE 35

A solution of5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-11,15-bis-THP-ether in acetone (10 ml) and 0.2 N aqueous oxalicacid (10 ml) was heated at 40° C. for 12 hours and then the acetone wasremoved in vacuum. The aqueous phase was extracted with ethyl acetate,and after washing until neutral, the organic layer was dried andevaporated to dryness. The residue was chromatographed on acid-washedsilica gel (30 g) and elution with methylene chloride-ethyl acetate(80:20) afforded5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid [α]_(D) =+19.5° (EtOH).

EXAMPLE 36

A solution of5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-11,15-bis-THP-ether (0.8 g) was dissolved in dry methanol (10 ml)and treated with p-toluenesulfonic acid (30 mg).

After 4 hours, the methanol was evaporated in vacuum and the oil waspartitioned between water and ethyl acetate. The organic layer waswashed with 2.5 ml of 5% NaHCO₃, water and evaporated to dryness.

The residue was absorbed on silica gel and eluted with benzene-ether(50:50) affording 0.48 g of methyl5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoate,[α]_(D) =+44.6° [α]₃₆₅ =+148° (EtOH).

A solution of this compound (0.2 g) was treated in aqueous methanol(20:80) with lithium hydroxide (0.04 g) for 4 hours at room temperature.

The methanol was removed in vacuum. The aqueous alkaline phase wasextracted with ethyl ether to remove impurities, then acidified to pH5.1 with aqueous NaH₂ PO₄ solution and extracted with ethyl ether.

These extracts were dried on Na₂ SO₄, evaporated to dryness affordingpure5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid, [α]_(D) =+46.7° [α]₃₆₅ =+155° (EtOH C=1%).

EXAMPLE 37

Using in the procedure of the Example 36 absolute ethanol as solvent todeacetalize, theethyl-5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoate,[α]_(D) =+42° (EtOH) was prepared.

EXAMPLE 38

Methyl5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoate,[α]_(D) =+15.7° (EtOH) was prepared by deacetalization of its11,15-bis-THP-ether (according to Example 35), followed by purificationon silica gel [4.5 g, using CH₂ Cl₂ :ethylacetate (65:35) as eluent].

EXAMPLE 39

Using in the procedure of Example 35 and 38, the free acid, the5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid, [α]_(D) =+15.6,[α]₃₆₅ =+53.4° (EtOH C=1%) was prepared.

EXAMPLE 40

Using in the deacetalization of a 9-hydroxy-11- or 11,15-acetalicprostynoic derivative prepared in the Examples 24-28, a polycarboxylicacid according to Examples 35,38 and 39, or a solution ofp-toluenesulfonic acid in a dry alcohol according to Examples 36 and 37and after purification on silica gel column, the following compoundswere prepared either as free acids or as methyl or ethyl esters:

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenyl-prost-5-en-13-ynoic acid; 5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(3'-trifluoromethyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(4'-methoxy)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19-ω-nor-18-phenyl-prost-5-en-13-ynoic acid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-15S-trihydroxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-benzyloxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15S-trihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(4'-fluoro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(3'-chloro)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(3'-trifluoromethyl)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(4'-methoxy)-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19-ω-nor-18-phenyl-prost-5-en-13-ynoic acid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-15R-trihydroxy-20,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-benzyloxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-(4'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,15R-trihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoicacid;

5c-9α11α,15R-trihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethylphenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α,15R-trihydroxy-20,19,18-trinor-17-(4'-fluoro)phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-ethoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-methoxy-20,19,18-trinor-16S-methyl-17-phenol-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-methoxy-10,19,18-trinor-16R-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15S-benzyloxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-ethoxy-29,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-methoxy-20,19,18-trinor-16S-methyl-17-phenyl-prost-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-methoxy-20,19,18-trinor-16R-methyl-17-phenyl-5-en-13-ynoicacid;

5c-9α,11α-dihydroxy-15R-benzyloxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid.

EXAMPLE 41

Using in the deacetalization of a 9-hydroxy-11- or 11,15-acetalicprost-ynoic derivative prepared in the Example 29, a poly-carboxylicacid according to Examples 35, 38 and 39, or a solution ofp-toluenesulfonic acid in a dry alcohol according to Examples 36 and 37and after purification on silica gel column, the following compoundswere prepared:

5c-9β,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-9-benzoate-methyl ester,

5c-9β,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid-9-benzoate-methyl ester,

5c-9β,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-9-benzoate-methyl ester,

5c-9β,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid-methyl ester,

5c-9β,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-ynoicacid-methyl ester,

5c-9β,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-ynoicacid methyl ester,

which by saponification with sodium hydroxide in aqueous ethanol underreflux were converted into the corresponding free hydroxy acids.

EXAMPLE 42

5c-1,9α,11α,15S-tetrahydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-yne,[α]_(D) =+49.8°[α]₃₆₅ =+128.5° (0.32 g) was obtained starting from asolution of the corresponding 1-carboxy-methyl ester (0.45 g) in dryethyl ether, which was added dropwise to a stirred solution of 0.06 g ofLiAlH₄ in ethyl ether, cooling to -2°+ +3°. After 3 hours, the excessreagent was destroyed by slow addition of aqueous saturated NH₄ Clsolution. The organic layer was separated, evaporated to dryness and theresidue was absorbed on silica gel (5 g). Elution bycyclohexane-ethylacetate afforded the compound. Same compound wasobtained starting from a solution of the5β-(2'-bromo-3'-S-hydroxy-5'-phenyl-pent-1'-trans-1'enyl)-2α,4.alpha.-dihydroxy-cyclopentane-1α-ethanal-γ-lactol-3',4-bis-THP-ether(0.8 g) in dry DMSO (5 ml) which was treated with the ylide prepared indry DMSO by adding a solution of potassium tert-butoxide (0.7 g) in DMSO(7 ml) to a stirred solution of triphenyl[5-(2'-tetrahydropyranyloxy)-pentyl]-phosphonium bromide in dry DMSO,cooled at 12°-14° C.

The mixture was maintained for 8 hours at room temperature, then wasdiluted with water and extracted with ethyl ether:pentane (1:1). Theorganic extracts were washed until neutral, dried on Na₂ SO₄, evaporatedand the residue was chromatographed on silica gel to afford5c-1,9α,11α,15S-tetrahydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-yne-1,11,15-tris-THP-ether(0.71 g).

A solution of this compound (0.34 g) was then treated in dry methanol(10 ml) with p-toluenesulfonic acid (10 mg). After 3 hours it wasevaporated to dryness affording the free tetrahydroxy compound, [α]_(D)=+40.8°.

EXAMPLE 43

A solution of5c-1,9α,11α15S-tetrahydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-yne-1,11,15-tris-THP-ether(0.42 g) in acetone (12 ml), cooled to -10+ -13°, was reacted with 0.8ml of Jones reagent and added dropwise to the stirred mixture. After 20minutes, the reaction was stopped by addition of excess benzene (80 ml)and the organic phase was washed with 35% aqueous (NH₄)₂ SO₄ solutionuntil neutral, and evaporated to dryness. The residual 9-oxo compoundwas dissolved in acetone (20 ml) and the solution was heated at 42° C.after addition of 0.15N oxalic acid (15 ml) for 14 hours. The excessacetone was evaporated in vacuum. The aqueous phase was extracted withethyl acetate and after chromatographic separation on silica gel (usingas eluent cyclohexane/ethylacetate 65:35),5c-9-oxo-1,11α,15S-trihydroxy-20,19,18-trinor-17-phenyl-prost-5-en-13-yne(0.16 g) was obtained.

EXAMPLE 44

Using the procedure of the Examples 42 and 43 the following compoundswere prepared:

5c-9-oxo-1,11α,15S-trihydroxy-16S-methyl-20,19,18-trinor-17-phenyl-prost-5-en-13-yne;

5c-9-oxo-1,11α-dihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-yne;

5c-1,9α,11α-trihydroxy-15S-methoxy-20,19,18-trinor-17-phenyl-prost-5-en-13-yne;

5c-1,9α,11α,15S-tetrahydroxy-16S-methyl-20,19,18-trinor-17-phenyl-prost-5-en-13-yne;

5c-1,9α,11α,15S-tetrahydro-29,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-yne;

5c-1,9α,11α,15S-tetrahydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-yne;

5c-1,9α,11α,15S-tetrahydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-yne;

5c-1,9α,11α,15S-tetrahydroxy-20,19,18,17-tetranor-16-(3'-m-chloro)-phenoxy-prost-5-en-13-yne.

We claim:
 1. An optically active or racemic PGF.sub.α compound of theformula ##STR39## wherein: R_(a) is hydrogen, C₁ -C₁₂ alkyl or a cationof a pharmaceutically of veterinarily acceptable base;one of R₄ and R₅is hydrogen and the other is hydroxyl or C₁ -C₆ alkoxy; R₆ is hydrogenor C₁ -C₄ alkyl; each of m₁ and m₂ is independently zero, 1, 2 or 3; Eis oxygen or sulphur R is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxyor C₁ -C₆ trihaloalkyl.
 2. A compound selected from the group consistingof:5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-phenoxy-prost-5-en-13-ynoicacid;5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(4'-fluoro)-phenoxy-prost-5-en-13-ynoicacid; 5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-chloro)-phenoxy-prost-5-en-13-ynoic acid;5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(3'-trifluoromethyl)-phenoxy-prost-5-en-13-ynoicacid;5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16(2'-fluoro)-phenoxy-prost-5-en-13-ynoicacid;5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16-(2'-methoxy)-phenoxy-prost-5-en-13-ynoicacid;5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16S-methyl-16-phenoxy-prost-5-en-13-ynoicacid;5c-9α,11α,15S-trihydroxy-20,19,18,17-tetranor-16R-methyl-16-phenoxy-prost-5-en-13-ynoicacid;and the salts and the lower alkyl esters thereof.
 3. Apharmaceutical or veterinary composition comprising a suitable carrierand/or diluent, and, as an active principle, a compound of claim 1.